Duration of Dual Anti-Platelet Therapy in Chronic Limb Threatening Ischemia After Distal Revascularization

Duration of Dual Anti-Platelet Therapy in Chronic Limb Threatening Ischemia After Distal Revascularization: a Randomized, Double-blind Trial PALADIN [PeripherAL Arterial DIsease Network] -DAPTCLTI

Chronic limb threatening ischemia (CLTI) is defined as ischemic foot pain at rest or non-healing foot wounds that is attributable to severe peripheral arterial disease (PAD).Revascularization is the cornerstone of therapy to relieve ischemic pain, prevent limb loss and preserve patient autonomy. Revascularization procedures often involve below-the-knee arterial disease in CLTI population. Dual antiplatelet therapy (DAPT, with aspirin, and clopidogrel) is recommended for at least 1-month after peripheral angioplasty. However, the exact duration of this DAPT remains controversial. Angioplasty of below-the-knee arteries is often followed by a longer period of DAPT, 3-months to one-year, due to a high risk of arterial thrombosis/stenosis.It will be the first trial on duration of DAPT in patients with below-the-knee angioplasty for CLTI, the end-stage of PAD

Chronic limb threatening ischemia (CLTI) is defined as ischemic foot pain at rest or non-healing foot wounds that is attributable to severe peripheral arterial disease (PAD). This condition is associated with increased risk of mortality and major amputation and has become a global health problem. Revascularization is the cornerstone of therapy to relieve ischemic pain, prevent limb loss and preserve patient autonomy. Revascularization procedures often involve below-the-knee arterial disease in CLTI population. Despite limb salvage procedure, recent reports still highlight the poor survival in this population. Mortality rate remains high, up to 25% of patients during the first year of follow-up after endovascular revascularization procedure. This poor overall survival isconstantly underlined in literature, with cardiovascular events as the main cause of death, followed by limb adverse events.

Dual antiplatelet therapy (DAPT, with aspirin, and clopidogrel) is recommended for at least 1-month after peripheral angioplasty. However, the exact duration of this DAPT remains controversial. Angioplasty of below-the-knee arteries is often followed by a longer period of DAPT, 3-months to one-year, due to a high risk of arterial thrombosis/stenosis. Current European or American guidelines are inconsistent concerning antithrombotic strategies after below-the knee revascularization. Most of the current antithrombotic strategy after PAD angioplasty is mainly extrapolated from coronary artery strategy. There is no randomized study after PAD revascularization in CLTI assessing the duration of DAPT. In the recent VOYAGER PAD study only 6.2% of the patients had a below-the-knee revascularization.

Antithrombotic management following below-the-knee revascularization procedure is thus challenging in everyday practice. Almost invariably, longer exposure to DAPT would lead to more bleeding, and the precise risk-to-benefit ratio can hardly be codified. We considered of paramount importance to adequately study the duration of DAPT in the most severe field of PAD. The design of PALADIN-DAPTCLTI, a randomized double-blind trial, will allow to assess the potential benefit of 12 months DAPT in patients with below-the-knee angioplasty and will carefully assess the safety of this strategy.

It will be the first trial on duration of DAPT in patients with below-the-knee angioplasty for CLTI, the end-stage of PAD.

Furthermore, despite limb salvage, patients with CLTI do not always experience sustained gain in their quality of life and repeat procedures likely adversely affect their health status. Along with other clinical endpoints and long-term cost effectiveness, patient-reported outcome in terms of quality of life in the post-procedural period will also be particularly relevant.

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 involving below-the-knee arteries (angioplasty/stenting) alone or combining above- and below-the-knee revascularization within the last 7 days prior to randomization
• 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.

(According to CTFG guidelines, a woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.)

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 inclusion, 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;
• Severe hepatic impairment or 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 and randomize the patient);
• Confirmed acute coronary syndrome (ACS) within 30 days prior to inclusion; Major trauma or accidents within 30 days prior to inclusion;
• 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);
• Other exclusion criteria :
• 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