Effect of One-Year versus One-Month Dual Antiplatelet Therapy Comprising Aspirin and Clopidogrel on Outcomes in Patients with Chronic Limb-Threatening Ischemia After Revascularization

Trial ID: 2025-524297-42-00
Protocol: PHRC-23-0035
Sponsor: Fondation Hopital Saint Joseph

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Diseases & Conditions

Peripheral arterial occlusive disease Peripheral artery angioplasty Peripheral artery thrombosis Angioplasty

Objectives

The primary objective of this study is to evaluate whether a 12-month duration of dual antiplatelet therapy, consisting of aspirin and clopidogrel, improves 1-year major amputation-free survival and overall mortality compared to a 1-month regimen in patients with chronic limb-threatening ischemia undergoing below-the-knee endovascular therapy. 5

Secondary objectives include the comparison of 12 months of dual antiplatelet therapy versus one month of therapy followed by aspirin monotherapy regarding the 12-month incidence of:

Individual components of the primary endpoint, including major amputation and mortality;
Major adverse limb events, comprising target lesion revascularization, acute limb ischemia, or major amputation of the index limb;
Major adverse cardiovascular events, including myocardial infarction, stroke, or cardiovascular death;
Major bleeding events as defined by the ISTH and clinically relevant non-major bleeding;
Net clinical benefit, a composite of death, major adverse limb events, major adverse cardiovascular events, and major bleeding.

Additional evaluations focus on changes in quality of life and 12-month cost-effectiveness and cost-utility.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients with chronic limb-threatening ischemia, specifically defined as Rutherford category 4 or 5. Eligible individuals are adults aged 18 years or older who have experienced ischemic rest pain or minor tissue loss for more than two weeks. Clinical assessment requires one or more abnormal hemodynamic parameters, such as an ankle-brachial index of less than 0.4, an absolute highest ankle pressure below 50 mm Hg, or an absolute toe pressure below 30 mm Hg. Participants must have undergone successful endovascular revascularization involving below-the-knee arteries within seven days of enrollment. Women of childbearing potential must provide a negative serum pregnancy test and utilize adequate contraception.

Plans and Procedures

This randomized, double-blind, controlled trial evaluates the duration of dual anti-platelet therapy (DAPT) in patients with chronic limb-threatening ischemia (CLTI) following distal revascularization. The study compares the efficacy and safety of one year of DAPT, consisting of aspirin and clopidogrel, against one month of DAPT. All participants will also receive standard care involving rivaroxaban. The methodology begins with a screening visit to assess eligibility based on Rutherford category 4 or 5 status, specific hemodynamic parameters, and successful endovascular revascularization. Following randomization, the primary endpoint is amputation-free survival assessed at 12 months. Secondary endpoints include overall mortality, target lesion revascularization, major adverse cardiovascular events (MACE), and various bleeding complications. Participant involvement extends for a total of 12 months to monitor clinical outcomes and quality of life via standardized questionnaires. The trial is designed to determine if extended therapy improves long-term survival and reduces major amputation rates compared to short-term therapy.

Treatment

The experimental treatment consists of clopidogrel administered as 75 mg film-coated tablets via the oral route. This medication is part of a dual antiplatelet therapy regimen intended for a duration of either one month or one year.

A placebo composed of lactose monohydrate is utilized in the study to maintain the double-blind design. All participants receive rivaroxaban at a dosage of 2.5 mg twice daily as part of the standard of care.

Efficacy

The primary efficacy endpoint is amputation-free survival at 12 months, which is defined as the duration from randomization until the occurrence of major amputation, specifically above-the-ankle amputation, or overall mortality from any cause.

Secondary endpoints evaluated at 12 months include:

The individual components of the primary endpoint: major amputation and overall mortality.
MALE, a composite endpoint comprising target lesion revascularization, acute limb ischemia, or major amputation of the index limb.
MACE, a composite endpoint consisting of myocardial infarction, stroke, or cardiovascular death.
Changes in quality of life from inclusion to 12 months, assessed using the VascuQoL-6 questionnaire and the EQ-5D-5L scale.
Major bleeding events, including fatal or symptomatic bleeding in critical areas, bleeding resulting in a hemoglobin decrease of 2 g/dL or more, or bleeding requiring transfusion of two or more units of blood.
Clinical impacts of bleeding, such as requiring medical or surgical intervention, resulting in hospitalization, or prompting medical evaluation.
Net clinical benefit, which is a composite outcome of deaths, MALE, MACE, and major bleeding events.
Economic parameters, including costs and the incremental cost-effectiveness and utility ratio.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥18 years
Hospitalized patients with CLTI defined as Rutherford category 4 (ischemic rest pain) or 5 (minor tissue loss, non-healing ulcer, focal gangrene) evolving for > 2 weeks + one or more abnormal hemodynamic parameters: ankle-brachial index (ABI) <0.4 (using higher of the dorsalis pedis and posterior tibial arteries), absolute highest ankle pressure <50 mm Hg, absolute toe pressure <30 mm Hg.
Successful endovascular revascularization within 7-days involving below-the-knee arteries (angioplasty/stenting) alone or combining above- and below-the-knee revascularization within the last 7 days
Affiliation to a French Health Insurance system.
Patient able to understand and sign a written informed consent form.
In women of childbearing potential: negative serum pregnancy test and use of adequate contraception.

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Exclusion Criteria

PAD Rutherford category 0, 1, 2, 3 or 6 (Rutherford 6 defined as severe ischemic ulcers or foot gangrene exceeding the digits)
Acute limb ischemia within one month prior to the qualifying revascularization
Platelet count < 100x109/L
Need for dual antiplatelet therapy for other reason than PAD
Need for concomitant treatment with anticoagulant (VKA or DOAC [except low dose rivaroxaban 2.5 mg x 2])
Known allergy or hypersensitivity to aspirin/clopidogrel
Exclusion criteria related to bleeding risks or systemic conditions:
Medical history or active clinically significant bleeding, lesions, or conditions within the last 6 months prior to randomization, considered to be a significant risk for major bleeding (this may include current medically confirmed gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, current or recent brain or spinal injury, known esophageal varices or major intraspinal or intracerebral vascular abnormalities);
Any known hepatic disease associated with coagulopathy or bleeding risk
Any condition requiring dialysis or renal replacement therapy or a renal impairment at screening assessed with an estimated glomerular filtration rate <15 mL/min/1.73 m2. If a patient's eGFR is <30 mL/min/1.73 m2 prior to the procedure, it must remain >15 mL/min/1.73 m2 72 hours after the procedure to enroll the patient);
Confirmed acute coronary syndrome (ACS) within 30 days prior to randomization
Major trauma or accidents within 30 days prior to randomization
Any medically documented history of intracranial hemorrhage, stroke, or transient ischemic attack (TIA)
Known active malignancy (as determined through review of medical history), excluding local skin cancer (basal or squamous cell carcinoma)
Poorly controlled diabetes (at the discretion of the investigator)
Severe uncontrolled hypertension (at the discretion of investigator)
Previous (within 30 days) or concomitant participation in another clinical interventional study (drug or device)
Close affiliation with the investigational site; e.g., a close relative of the investigator, dependent person (e.g., employee or student of the investigational site)
Expected impossible follow-up or poor compliance
Patient deprived of liberty
Patient under tutorship, curatorship, or legal protection
Documented pregnancy or lactation