Peripheral Arterial Disease
Conditions
Keywords
peripheral arterial disease, antiplatelet therapy
Brief summary
The purpose of this study is to evaluate whether clopidogrel 75 mg daily on a background of aspirin 75-100 mg/d for clinically indicated duration or for an additional 12 months will lead to an increased rate of primary patency, limb salvage, non-fatal myocardial infarction (MI), ischemic stroke, and survival, in patients receiving endovascular treatment of PAD at end of study treatment.
Detailed description
Peripheral arterial disease (PAD) is extremely prevalent worldwide and affects over 206 million people. Over 36 million patients with PAD are estimated to be present in the United States. Percutaneous revascularization therapies have evolved dramatically, yet the long-term success of these therapies remains modest and the morbidity and mortality associated with PAD remains high, with up to 30% mortality risk at 5 years. Nearly, 3.2 million endovascular procedures are performed annually. Though, this exceeds interventional procedures performed for coronary artery disease (CAD), the current PAD guidelines are silent regarding the need and optimal duration of antiplatelet therapy (APT) for patients following an endovascular procedure for claudication or critical limb ischemia (CLI). The lack of data and clinical studies is by far the greatest impediment to the formulation of such guideline recommendations critically needed by providers and patients alike, especially given the current limited durability of lower extremity endovascular procedures. The objective of this trial is to evaluate whether clopidogrel 75 mg QD on a background of ASA 75-100 mg/d for clinically indicated duration or for an additional 12 months will lead to an increased rate of primary patency, limb salvage, non-fatal myocardial infarction (MI), ischemic stroke, and survival, in patients receiving endovascular treatment of PAD at end of study treatment. The investigators hypothesize that dual antiplatelet therapy (DAPT) with ASA and clopidogrel administered for an additional 12 months following iliac, femoropopliteal or below the knee endovascular intervention will improve primary patency, limb salvage, freedom from ischemic stroke and survival, in patients with symptomatic PAD. Clinical endpoints will be analyzed in all subjects who are enrolled, regardless of whether the trial treatment administered successfully completed for the desired duration. A subject will be considered enrolled in the trial when he/she is randomized to one of the treatment arms of the study. All endpoints are subject-based unless otherwise specified. The primary endpoint is subject-based of the longer of a 12-month or end of study treatment endpoint of the first occurrence of index limb arterial occlusion, surgical intervention, endovascular intervention, amputation of the affected limb (primary patency and limb salvage), MI, ischemic stroke or death (survival). The secondary endpoints are subject-based on the longer of a 12 month or end of study treatment endpoints that include: (a) the first occurrence of any individual component of the primary endpoint, (b) the first occurrence of the following during follow-up: cardiovascular death, or MI, or ischemic stroke, or any amputation above the ankle and (c) severe bleeding defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification. The tertiary endpoint is based on the longer of a 12-month or end of study moderate bleeding according to the GUSTO classification.
Interventions
DRUGClopidogrel
Clopidogrel 75 mg once daily for clinically indicated duration or for clinically indication duration + 12 months
Acetylsalicylic acid (ASA) 75-100 mg once daily for clinically indicated duration or for clinically indication duration + 12 months
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
General: * Signed informed consent * At least 18 years old * Documented symptomatic iliac, femoropopliteal (FP) or below-the knee artery (BTK) atherosclerotic disease (Rutherford/Becker category 2, 3 or ≥4) * Undergone clinically indicated uncomplicated endovascular intervention to one or more locations of the iliac, femoropopliteal below-the knee arteries * Estimated survival ≥1 year in the judgment of the primary operator * Pre-index procedure use of ASA, clopidogrel or both at any dose Angiographic: * De novo or restenotic lesions in the common and/or external iliac artery, superficial femoral artery (SFA), popliteal artery, tibio-peroneal (TP) trunk, anterior tibial (AT) artery, peroneal artery (PA) or posterior tibial (PT) artery (applies to all target lesions if multiple) * Subjects with multiple planned procedures can be enrolled after the completion of the last planned procedure.
Exclusion criteria
General: * Complicated qualifying procedure (perforation, flow limiting dissection, distal embolization requiring re-intervention, need for repeat endovascular, surgical revascularization, amputation or blood transfusion prior to hospital discharge following an index procedure * Extended hospital stay \>7 days following the index procedure * Allergy to aspirin or clopidogrel * Life expectancy less than 12 months due to other medical co-morbid condition(s) that could limit the subject's ability to participate in the trial, limit the subject's compliance with the follow-up requirements, or impact the scientific integrity of the trial * Known hypersensitivity or contraindication to contrast dye that, in the opinion of the investigator, cannot be adequately pre-medicated. * Intolerance to antiplatelet, anticoagulant, or thrombolytic medications * Platelet count \<90,000 mm3 or \>600,000 mm3 * Serum creatinine \>2.5 mg/dL * Dialysis-dependent end stage renal disease * Pregnancy * Current participation in another drug or device trial that requires interruption of dual-antiplatelet therapy with aspirin or clopidogrel for the duration of the study * Planned surgeries, endovascular or other non-vascular or cardiac procedures * Concurrent warfarin or other chronic oral anticoagulant therapy * Contraindication(s) to the use of AT (history of intra-cerebral bleed, presence of intra-cerebral mass, recent or \<6 weeks gastrointestinal bleed, blood transfusion within the last 6 weeks, any trauma requiring surgery or blood transfusion within the last 4 weeks or any surgical procedure within the last 4 weeks. Angiographic: * Endovascular intervention to iliac, femoropopliteal or BTK artery bypass graft * Persistent, intraluminal thrombus of the proposed target lesion at the completion of the index procedure * Perforated vessel as evidenced by extravasation of contrast media * Vascular graft, aneurysm or postsurgical stenosis of the target vessel
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Occurrence of Target Vessel Occlusion, Surgical Revascularization, Endovascular Revascularization, Major Amputation of Target Limb, Ischemic Stroke, MI, or Death | 12 months from index procedure or end of study treatment, whichever is longer, assessed up to 2 years | Occlusion of the target vessel documented by any imaging procedure (eg, Duplex ultrasonography scan including B mode imaging and Doppler ultrasound scan) at any follow-up visit within 12 months or end of study treatment period, whichever is longer. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Occurrence of Bleeding | 12 months from index procedure or end of study treatment, whichever is longer, assessed up to 2 years | Any mild, moderate, severe, or life-threatening bleeding. Severe or Life-threatening: Intracerebral hemorrhage Resulting in substantial hemodynamic compromise requiring treatment Moderate: Requiring blood transfusion but not resulting in hemodynamic compromise Mild: Bleeding that does not meet above criteria Severe bleeding defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DAPT - Clinically Indicated Duration+12m Clopidogrel 75 mg daily and Acetylsalicylic acid (ASA) 75-100 mg daily for clinically indicated duration plus an additional 12 months
Clopidogrel: Clopidogrel 75 mg once daily for clinically indicated duration or for clinically indication duration + 12 months
Acetylsalicylic acid (ASA): Acetylsalicylic acid (ASA) 75-100 mg once daily for clinically indicated duration or for clinically indication duration + 12 months | 77 |
| DAPT - Clinically Indicated Duration Clopidogrel 75 mg daily and Acetylsalicylic acid (ASA) 75-100 mg daily for clinically indicated duration with a minimum of 30 days
Clopidogrel: Clopidogrel 75 mg once daily for clinically indicated duration or for clinically indication duration
Acetylsalicylic acid (ASA): Acetylsalicylic acid (ASA) 75-100 mg once daily for clinically indicated duration or for clinically indication duration | 82 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 4 |
Baseline characteristics
| Characteristic | DAPT - Clinically Indicated Duration+12m | DAPT - Clinically Indicated Duration | Total |
|---|---|---|---|
| Age, Continuous | 65.62 years STANDARD_DEVIATION 8.82 | 65.27 years STANDARD_DEVIATION 8.9 | 65.44 years STANDARD_DEVIATION 9 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 26 Participants |
| Sex: Female, Male Male | 65 Participants | 68 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 77 | 4 / 82 |
| other Total, other adverse events | 1 / 77 | 1 / 82 |
| serious Total, serious adverse events | 27 / 77 | 37 / 82 |
Outcome results
Primary
Number of Participants With First Occurrence of Target Vessel Occlusion, Surgical Revascularization, Endovascular Revascularization, Major Amputation of Target Limb, Ischemic Stroke, MI, or Death
Occlusion of the target vessel documented by any imaging procedure (eg, Duplex ultrasonography scan including B mode imaging and Doppler ultrasound scan) at any follow-up visit within 12 months or end of study treatment period, whichever is longer.
Time frame: 12 months from index procedure or end of study treatment, whichever is longer, assessed up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DAPT - Clinically Indicated Duration+12m | Number of Participants With First Occurrence of Target Vessel Occlusion, Surgical Revascularization, Endovascular Revascularization, Major Amputation of Target Limb, Ischemic Stroke, MI, or Death | 13 Participants |
| DAPT - Clinically Indicated Duration | Number of Participants With First Occurrence of Target Vessel Occlusion, Surgical Revascularization, Endovascular Revascularization, Major Amputation of Target Limb, Ischemic Stroke, MI, or Death | 16 Participants |
Secondary
Number of Participants With First Occurrence of Bleeding
Any mild, moderate, severe, or life-threatening bleeding. Severe or Life-threatening: Intracerebral hemorrhage Resulting in substantial hemodynamic compromise requiring treatment Moderate: Requiring blood transfusion but not resulting in hemodynamic compromise Mild: Bleeding that does not meet above criteria Severe bleeding defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification.
Time frame: 12 months from index procedure or end of study treatment, whichever is longer, assessed up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DAPT - Clinically Indicated Duration+12m | Number of Participants With First Occurrence of Bleeding | 5 Participants |
| DAPT - Clinically Indicated Duration | Number of Participants With First Occurrence of Bleeding | 4 Participants |
p-value: 0.6595Cochran-Mantel-Haenszel