Antiplatelet Strategy for Peripheral Arterial Interventions for Revascularization of Lower Extremities

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.

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